Millennium Pharmaceuticals, Inc. (MLNM) Message Board

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM)

Public Reply Prvt Reply Mark as Last Read File

Previous 10 Next 10 Previous Next

To: tuck who wrote (2289)	12/21/2004 11:15:03 AM
From: tuck	Read Replies (1) of 3044

[VHL expression in renal cell carcinoma sensitizes to bortezomib] >>Oncogene. 2004 Dec 20; [Epub ahead of print] VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-kappaB-dependent mechanism. An J, Fisher M, Rettig MB. 1VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. In renal cell carcinomas (RCC), NF-kappaB blockade is required for maximal bortezomib-induced apoptosis, and expression of the von Hippel-Lindau (VHL) tumor suppressor protein downregulates NF-kappaB. Thus, we hypothesized that expression of wild-type (wt) VHL sensitizes RCC cells to bortezomib by reducing constitutive NF-kappaB activity. Using isogenic paired cell lines with and without expression of wtVHL, we have confirmed that VHL expression reduces constitutive NF-kappaB activity. Moreover, VHL expression confers markedly heightened sensitivity to the growth inhibitory effects of bortezomib in vitro. The bortezomib IC(50) values were greater than two logs lower in the VHL-expressing cell lines compared to the VHL-deficient counterparts. By manipulating the level of constitutive NF-kappaB activity in an isogenic pair of RCC cell lines independently of VHL expression, we were able to demonstrate that the VHL sensitization effect is due to downregulation of NF-kappaB activity. These findings offer the enticing possibility of using VHL status as a molecular marker to identify RCC patients who may be sensitive to bortezomib. In particular, RCC patients who have non-clear-cell histologies as well as approximately 25% of clear-cell RCCs manifest expression of wtVHL and represent a subpopulation of patients that is apt to respond to bortezomib.<< Personalized medicine . . . Cheers, Tuck

Report TOU Violation

Share This Post

Public Reply Prvt Reply Mark as Last Read File

Previous 10 Next 10 Previous Next